Erectile dysfunction (ED) is a devastating complication of treatment for prostate cancer. Post-radical prostatectomy ED (pRP-ED) is a major quality of life issue with social and financial ramifications for patients. All treatments for pRP-ED are met with significantly lower success rates when compared to other ED groups (i.e., diabetes, etc). This complication occurs despite attempts to preserve cavernous nerve (CN) integrity with bilateral or unilateral nerve-sparing prostatectomies. The exact mechanism involved with post-radical prostatectomy (pRP) ED is not clear other than the obvious CN nerve interruption during dissection and the development of penile fibrosis. It is currently thought that postoperative penile fibrosis despite normal arterial flow is the cause of ED. If we are to impact the incidence of this complication and improve the chances of successful rehabilitation, then a better understanding of the mechanism of injury is required. This will require knowledge of the molecular signaling events responsible for pRP-ED. Once the mechanisms are elucidated avenues for intervention and prevention will be expanded. Our goal is to characterize the molecular mechanisms of pRP-ED using our animal model. We postulate that pRP-ED is a result of downregulated NOS-I, TGF beta 1 and ET-1. We hypothesize that downregulated penile TGF beta 1 and ET-1 induce a cascade of molecular events that culminate in the loss of penile smooth muscle (SM) cells and their replacement with a less compliant extracellular matrix (ECM) (fibrosis). Four specific aims are proposed: 1) to test the hypothesis that nitric oxide synthase isoforms are altered after CN injury and result in a decreased TGF beta 1; 2) to test the hypothesis that expression of NOS-I and NOS-II in CN injured penes is downregulated; 3) to test the hypothesis that protein content and expression of ET-1 and ET-B receptor are decreased with CN injury; 4) to test the hypothesis that the CN injury impacts the percent of SM, ECM and fibrosis. Results will aid the understanding of how CN injury contributes to ED and elucidate preventative mechanisms.